Chronic myelogenous leukemia (CML) accounts for approximately 20% of all leukemia cases. The chromosomal translocation known as the Philadelphia chromosome is a specific genetic abnormality in leukemia cancer cells. In this translocation, a single multipotent hematopoietic stem cell undergoes genetic rearrangement between two chromosomes (the 9th and 22nd). As a result, part of the BCR (“breakpoint cluster region”) gene from chromosome 22 is fused with the ABL (Abelson leukemia) gene on chromosome 9. This abnormal “fusion” gene generates a protein of p210 or sometimes p185 weight (p210 is short for 210 kDa protein, a shorthand used for characterizing proteins based solely on size). Because ABL carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the BCR-ABL fusion gene product is also a tyrosine kinase.
BCR-ABL activates a cascade of proteins that control the cell cycle, speeding up cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia.
With improved understanding of the nature of the BCR-ABL protein and its action as a tyrosine kinase, targeted therapies that specifically inhibit the activity of the BCR-ABL protein, have been developed, the first of which was imatinib mesylate. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of BCR-ABL as the cause of CML.
Nilotinib is a phenylaminopyrimidime derivative structurally related to imatinib that selectively inhibits the BCR-ABL tyrosine kinase.
Nilotinib is chemically termed as 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide and has the structural formula I:

Nilotinib and its process of preparation are disclosed in U.S. Pat. No. 7,169,791 B2.
A particularly useful salt of nilotinib is nilotinib hydrochloride monohydrate as disclosed in U.S. Pat. No. 8,163,904 B2. This patent discloses two polymorphic forms of nilotinib hydrochloride monohydrate namely, “Form A” and “Form B”. The patent also discloses various other salts of nilotinib, namely monophosphate, diphosphate, sulfate, mesylate, esylate, besylate and tosylate and processes for their preparation. Example 1 of U.S. Pat. No. 8,163,904 describes a process for preparing nilotinib hydrochloride monohydrate, the resulting product of which is characterized by an X-Ray diffraction (XRD) pattern having peaks at 7.4, 9.4, 11.6, 12.1, 15.8, 19.3, 22.1, 24.1 and 25.7±0.2°2θ. Form B is described in U.S. Pat. No. 8,163,904 as being hygroscopic and very slightly soluble in water.
WO2011/033307 discloses nilotinib dihydrochloride dihydrate characterized by XRD, Differential scanning calorimetry (DSC) and Thermogravimetric analysis (TGA). Also disclosed are processes of preparation and pharmaceutical compositions containing these compounds as well as the use of the compounds in the treatment of cancer. Nilotinib dihydrochloride dihydrate disclosed in WO2011/033307 is characterised by (i) an XRD pattern comprising peaks at 7.18, 14.32, 23.34 and 27.62±0.2°2θ; and (ii) a DSC thermogram with endothermic peaks at about 107±2° C. and 251±2° C.
One important property associated with solid state forms of drug substances is their aqueous solubility. Compounds having poor water solubility can lead to limited oral bioavailability when administered in patients. In such cases, the discovery of new polymorphic forms and solvates of a pharmaceutically useful compound with improved aqueous solubility provides a significant opportunity to increase the performance characteristics of the active pharmaceutical ingredient (API). The increase in performance may be seen in oral bioavailability, flowability and solubility thus reducing the dosage required for the patient.
There is a continued need to contribute towards enhancing the properties of nilotinib, particularly with respect to solubility and industrial feasibility.